This proposal will address itself to the general question: What role does the autonomic system play in modifying insulin release and maintaining B cell functional integrity? This question will be approached along three interdependent lines of enquiry. First, extension of previous observations regarding the effect of adrenergic and cholinergic agents on modifying insulin release dynamics, including assessment of the effect of adrenergic agents on cholinergically induced insulin release utilizing the in vitro perfusion technique. This work will also investigate the in vivo effect of 6 OH dopamine sympathectomy on in vivo and in vitro insulin release characteristics. Second, investigate the role of Ca ions in mediating the defined effects of autonomic agents on insulin release in vitro. This will involve: standardization of experimental design such that net Ca ions influx and Ca ions efflux from islets can be directly compared utilizing Ca45, use of Lanthanum (to define levels of Ca ions membrane binding) and of tritiated Mannitol (to assess extracellular space and therefore E/C Ca45 in islets). Third, to further explore the effect of diazoxide in protecting against chemical diabetes. This will involve first the definition of the dose response curve to streptozotocin as assessed by glucose tolerance and insulin response to glucose in vivo, pancreatic insulin content after in vivo injection and the modification made by diazoxide plus or minus agents such as alpha and beta adrenergic blockers. The second section will involve the use of various agents to modify the effect of diazoxide in protecting against streptozotocin induced B cell death in vitro in cultured islets as assessed by in vitro insulin release and electronmicroscopy.